The amyloid β protein (“Aβ protein”) is considered to be one of the proteins that cause Alzheimer's disease. Particularly, the accumulation of the Aβ protein in the brain is recognized as one of the pathological hallmarks of Alzheimer's disease. Accumulation of Aβ protein in the brain forms a rigid fibrous molecular structure. It is believed that this causes the death of neurons in the brain, damaging neural function and, as a result, causing the onset of Alzheimer's disease.
Aβ protein is formed in such a manner that an amyloid precursor protein (or “APP”), which is a transmembrane protein, is cleaved by β-secretase to form βCTF, which is also a transmembrane protein, and the βCTF is further cleaved by γ-secretase to form the Aβ protein. The Aβ protein thus formed is believed to be released from the cell membrane and accumulate in the brain.
It is known that the βCTF cleaved by γ-secretase is divided into Aβ protein and AICD, and it is also known that sAPPβ is released when the APP is cleaved by β-secretase (FIG. 1).
Based on the matured APP, Aβ protein corresponds to the 653rd to 694th amino acid residues, and βCTF corresponds to the 653rd to 751st amino acid residues. The sAPPβ corresponds to the 18th to 652nd amino acid residues and AICD corresponds to the 701st to 751st amino acid residues.
For the reasons described above, a γ-secretase inhibitor was believed to be effective in inhibiting the accumulation of Aβ protein, which is a protein that causes Alzheimer's disease.
However, γ-secretase, which is known as a complex comprising Pen-2, presenilin, nicastrin, and Aph-1 each being a transmembrane protein, is a aspartic protease that recognizes, as the substrate, not only the APP mentioned above but also transmembrane proteins, such as APLP1, APLP2, Notch, Jagged2, Delta1, E-cadherin, N-cadherin, CD44, ErbB4, Nectin1, and LRP1; receptors; etc.
Accordingly, if L-685,458, DAPT, LY-411,575, and like γ-secretase inhibitors are used to inhibit the production of Aβ protein, the enzyme activity of γ-secretase as a protease against the proteins other than βCTF will also be inhibited; therefore, use of such an inhibitor without modification as a drug may cause undesirable side effects.
For example, it has been reported that LY-411,575, which is one of the γ-secretase inhibitors, induces atrophy of the thymus and reduces the number of mature B cells in the spleen. If such an inhibitor is used as a pharmaceutical composition without modification, there is a risk that this may trigger side effects in immunity, etc. (NPL 1). Furthermore, it has been reported that lowering the enzyme activity of γ-secretase itself may cause skin abnormalities, squamous cancer, spleen hypertrophy, and the like (NPL 2).
Considering the production mechanism of Aβ protein, use of a compound that inhibits the enzyme activity of β-secretase also may be effective. However, there is a report that such use will decrease the number of births of β-secretase knockout mice; therefore, use of such a compound as a drug for Alzheimer's disease is not preferable.
There are findings that nonsteroidal anti-inflammatory drugs (or “NSAIDs”) are effective in inhibiting the production of Aβ protein. However, it is also known that these drugs are not effective for some familial Alzheimer's diseases (e.g., those associated presenilin mutations) (NPL 3). Furthermore, γ-secretase isolated from patients with mild cognitive impairment or Alzheimer's disease exhibits change in its activity, indicating that the effect of the γ-secretase modulator that reduces the production of Aβ42 is low (NPL 4).
γ-Secretase-dependent cleavage of βCTF fused with FLAG tag at the N-terminus is not observed in the presence of anti-FLAG antibody (Non-patent Literature 5).